It is well-established that induction of fetal hemoglobin (Hb F) can ameliorate the clinical complications of sickle cell disease, that any increment in-Hb F provides some clinical benefit, but high Hb F levels equal to or > 20% are usually required to prevent organ damage. The chemotherapeutic agent Hydroxyurea (HU) induces Hb F to a mean level of 8.6% in adult patients, and reduces the incidence of painful crises and acute chest syndrome, with half of adult patients responding. Additional therapeutics which induce Hb F to high levels are still needed for definitive treatment of sickle cell disease. In pilot studies, a Pulsed regimen of Arginine Butyrate (AB) induced Hb F in 9/11 adult patients to a mean level of 21%. When AB was added to HU, further induction of Hb F, by a mean 14.8% above the Hb F levels on HU alone was observed in 5/5 patients. While HU is considered to stimulate Hb F through effects on erythroid cell kinetics, Butyrate transcriptionally activates the gamma globin gene promoter in reporter assays. In some patients who have rapid high Hb F responses to AB, polysome analysis demonstrates increased efficiency of gamma globin mRNA translation. HU and AB, therefore, appear to induce Hb F through different mechanisms. Based on these findings, we hypothesize that 1) combined therapy with HU + Pulsed AB will induce higher levels of Hb F than the levels achieved with HU alone, and 2) further investigation of translational mechanisms of Hb F induction by AB will provide a basis for designing more effective regimens of administration of Butyrate. A multi-center Phase II clinical trial of HU + AB in sickle cell patients is proposed to test these hypotheses.